TRF2 protects human telomeres from end-to-end fusions.
The mechanism by which telomeres prevent end-to-end fusion has remained elusive. Here, we show that the human telomeric protein TRF2 plays a key role in the protective activity of telomeres. A dominant negative allele of TRF2 induced end-to-end chromosome fusions detectable in metaphase and anaphase cells. Telomeric DNA persisted at the fusions, demonstrating that TTAGGG repeats per se are not sufficient for telomere integrity. Molecular analysis suggested that the fusions represented ligation of telomeres that have lost their single-stranded G-tails. Therefore, TRF2 may protect chromosome ends by maintaining the correct structure at telomere termini. In addition, expression of mutant forms of TRF2 induced a growth arrest with characteristics of senescence. The results raise the possibility that chromosome end fusions and senescence in primary human cells may be caused by loss by TRF2 from shortened telomeres.
van Steensel
B
B
The Rockefeller University, New York, New York 10021, USA.
Smogorzewska
A
A
de Lange
T
T
D000705:Anaphase; D002455:Cell Division; D016922:Cellular Senescence; D002869:Chromosome Aberrations / Q000235:genetics*; D004247:DNA / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005354:Fibrosarcoma; D006151:Guanosine / Q000032:analysis; D006367:HeLa Cells; D006801:Humans; D008677:Metaphase; D011993:Recombinant Fusion Proteins; D012091:Repetitive Sequences, Nucleic Acid; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000235:genetics*; D035341:Telomeric Repeat Binding Protein 2; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D011993:Recombinant Fusion Proteins; D035341:Telomeric Repeat Binding Protein 2; D006151:Guanosine; D004247:DNA; D019098:Telomerase